Project Summary The implantable cardioverter defibrillator (ICD) is the most effective means of detecting and treating arrhythmias, such as ventricular tachycardia (VT) or ventricular fibrillation (VF). However, the main limitation of the current ICD technology is that it aims to terminate an arrhythmia only after the arrhythmia has started. Given that failure, delay or false decision in detecting VT/VF are life-threatening concerns, the next generation of ICD technology should be able to prevent arrhythmias from starting, rather than terminating them after their initiation. Repolarization alternans (RA), a pattern of variation in the shape of electrocardiographic waveform that appears on an every other beat basis, has been associated with increased vulnerability to VT/VF and sudden cardiac death (SCD). In this paradigm shift grant application we propose to investigate the hypothesis that therapy application by an ICD before the abnormal heart rhythm develops will provide a significant improvement not only in preventing SCD, but also in patient acceptance of ICD therapy and quality of life. We have developed a prototype system that can both estimate RA in real-time from intracardiac electrograms and deliver electrical pulses that are timely coupled to cardiac electrical activity. In this proposal we will investigate the applicability of RA-triggered delivery of clinically appropriate electrical therapy to suppress/terminate RA and prevent the development of VT/VF in an animal model of ischemic cardiomyopathy in ambulatory animals. To achieve the aims of this proposal we will (i) determine the efficacy of timely delivered pacing pulses in reducing/suppressing repolarization alternans and preventing the onset of ventricular tachyarrhythmias; (ii) determine whether altered heart rate variability reduces/suppresses repolarization alternans and prevents the onset of ventricular tachyarrhythmias; (iii) determine whether RA-triggered therapy can reduce/suppress repolarization alternans and prevent the onset of ventricular tachyarrhythmias in ambulatory animals.